At the age of twenty-two, on the invitation of his brother-in-law, Verbeck traveled to the United States to work at a foundry located outside of Green Bay, Wisconsin, which had been developed by Moravian missionaries to build machinery for steamboats. Verbeck stayed in Wisconsin for almost a year, during which time he changed the spelling of his name from "Verbeek" to "Verbeck" in the hope that Americans could better pronounce it. However he wanted to see more of America and moved to Brooklyn, New York where his sister had previously lived. He then decided to work as a civil engineer in Arkansas, and designed bridges, structures and machines. However, in Arkansas he was deeply moved by the lives of slaves in the southern plantations, and the teachings of H.W. Beecher, a preacher whose sister was Harriet Beecher Stowe, writer of Uncle Tom's Cabin. After almost dying from cholera, he swore that he would become a missionary if he recovered. In 1855 he entered a seminary in Auburn, New York, where many Dutch had immigrated.

Verbeck also taught foreign languages, politics, and science at the Yōgakusho (School for Western Studies) in Nagasaki, from August 1864. Initially he taught two hours a day, five days a week. Soon there were more than one hundred students at the school. Verbeck's pupils included Ōkuma Shigenobu, Itō Hirobumi, Ōkubo Toshimichi, Sagara Tomoyasu (Chian), and Soejima Taneomi. In 1865, French and Russian were added to the curriculum, and the school was renamed Gogakusho (Language School). In September of that same year the school was moved again and given the name Seibikan. Here, Verbeck taught both German and English classes. The texts that he preferably used were the American Declaration of Independence and the Constitution.

Verbeck cooperated with Takahashi Shinkichi to publish the Satsuma Dictionary. The first edition was printed by the American Presbyterian Mission Press in Shanghai. In 1873, a revised edition was printed in Tokyo.

Verbeck also served as a counselor of the Meiji government under Sanjō Sanetomi. In close cooperation with Sagara Tomoyasu (Chian), one of his former pupils, Verbeck recommended German medicine as a model for modern medical education and practice in Japan. He was also often consulted about the establishment of the prefectural system of local administration and influential in encouraging the dispatch of the Iwakura mission, the first Japanese diplomatic mission to the United States and Europe

As the ban of Christianity in Japan was lifted in February 1873, Verbeck was permitted to resume his missionary efforts.

Verbeck made a trip to Europe on 6 months' leave given by the Japanese government and traveled to meet up with the Iwakura Mission. On his return to Japan, he resigned from the university, and spent the next few years as a translator of English legal documents into Japanese.

Verbeck attempted to return to the United States in 1890 with his daughter, but was refused by the American government, as he could not prove his Dutch nationality and his application for American nationality based on his previous stay in the United States was denied. The Japanese government responded by granting Verbeck permanent residency and issuing him a passport.

Griffis, William Elliot. (1900). Guido Verbeck of Japan: A citizen of no country; a life story of foundation work inaugurated by Guido Fridolin Verbeck. Chicago: Fleming H. Revell. [reprinted by Oliphant, Anderson & Ferrire, London, 1901.]